This invention relates generally to the field of lipid metabolism, and more specifically to the field of absorption of lipids from the gut.
The absorption of lipid molecules from the intestinal tract is hindered in certain disease conditions, including cystic fibrosis (CF), Graves disease, celiac disease, diabetes mellitus, and cachexia. This malabsorption of dietary fats can manifest itself in excess fat in the stools, a condition known as steatorrhea. Fat absorption in cystic fibrosis patients can be severely affected and 30 to 60 percent of ingested fat can be malabsorbed. The malabsorption and resulting steatorrhea are generally not successfully handled by the oral administration of pancreatic lipase. In an effort to control the steatorrhea, the patient may consume less fat than desirable for good health.
Malabsorption of fats leads to nutritional deficiencies and wasting, prompting therapeutic measures to boost fat uptake. In conditions such as CF where the secretion of pancreatic enzymes is insufficient to supply adequate lipases to break down lipids in the gastrointestinal tract, therapeutic measures include the administration of pancreatic enzymes containing lipases. These treatments are insufficient to provide adequate fat digestion to supply the nutritional needs of all such subjects.
Limited body fat is also found frequently in aged and physically stressed individuals. Such individuals also would benefit from methods which increase intestinal fat uptake from dietary sources.
It has now been discovered that the absorption of dietary fats in the intestine can be increased by increasing the amount of lysophosphatidylcholine in the intestine. It is believed that increased lysophosphatidylcholine acts as a carrier for fats by forming a complex with the fats to increase transport across the membrane into enterocytes which line the intestinal wall. It is believed that increased lysophosphatidylcholine drives the absorption of fats by providing additional material to complex the fat molecules.
According to one aspect of the invention, methods for increasing fat absorption from the intestine of a subject are provided. The methods include administering to a subject in need of such treatment an agent which increases lysophosphatidylcholine in the intestine in an amount effective to increase fat absorption. In certain embodiments the agent comprises an isolated complex of lysophosphatidylcholine and lipid molecules selected from the group consisting of monoglycerides, fatty acids, diglycerides, triglycerides, cholesterols, cholesterol esters, polyglycerol fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters and glycerol. In some embodiments the isolated complex includes lysophosphatidylcholine, monoglyceride and fatty acid. Preferably the molar ratio of lysophosphatidylcholine:the sum of monoglyceride and fatty acid in the isolated complex is between 1:3 and 1:12, and more preferably still the molar ratio of lysophosphatidylcholine:the sum of monoglyceride and fatty acid in the isolated complex is between 1:5 and 1:6, more preferably between 1:4:2 and 1:2:4. Still more preferably the isolated complex has a lysophosphatidylcholine:monoglyceride:fatty acid molar ratio selected from the group consisting of 1:4:2, 1:3:3 and 1:3:2. In other embodiments the agent comprises phospholipase A2. Preferably, the agent further comprises a lipid selected from the group consisting of phosphatidylcholine, lysophosphatidylcholine, monoglycerides, fatty acids, diglycerides, triglycerides, cholesterols, cholesterol esters, polyglycerol fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters and glycerol. In other preferred embodiments, the agent includes an isolated complex of phospholipase A2 and phosphatidylcholine. Preferably the agent further includes an isolated complex of lysophosphatidylcholine, monoglyceride and fatty acid, particularly wherein the isolated complex has a lysophosphatidylcholine:monoglyceride:fatty acid molar ratio between 1:4:2 and 1:2:4. In still other embodiments, the agent is administered orally. In further embodiments, the serum concentration of lipids is increased. Preferably, the serum concentration of at least one lipid not administered to the subject as part of the agent is increased. In additional embodiments, the agent is formulated to enter the intestine of the subject without substantial degradation; preferably the agent is enteric coated.
According to another aspect of the invention, compositions including phospholipase A2 formulated for oral delivery to a subject are provided. In some embodiments the composition includes phospholipase A2 and a pharmaceutically acceptable carrier. In other embodiments, the composition is enteric coated. In still other embodiments, the compositions also include lipid molecules selected from the group consisting of phosphatidylcholine, lysophosphatidylcholine, monoglycerides, fatty acids, diglycerides, triglycerides, cholesterols, cholesterol esters, polyglycerol fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters and glycerol. In yet other embodiments, the compositions include an isolated complex of lysophosphatidylcholine, monoglyceride and fatty acid. Preferably the isolated complex has a lysophosphatidylcholine:monoglyceride:fatty acid molar ratio between 1:4:2 and 1:2:4, more preferably the lysophosphatidylcholine:monoglyceride:fatty acid molar ratio is selected from the group consisting of 1:4:2, 1:3:3 and 1:3:2.
The use of the foregoing compositions in the preparation of medicaments, particularly medicaments for the treatment of cystic fibrosis also is provided.
These and other objects of the invention will be described in further detail in connection with the detailed description of the invention.